d (-)-n-tert.butyl- and -n-isopropyl-1-phenyl-2-amino-ethanols



2 Claims. (03260-5706) The present invention relates to novelanti-diuretic compounds useful in therapy and to their production andmore particularly, to d()-N-alkyl-l-phenyl-Z-aminoethanols havingspecific activity for inhibiting excretion of water and salts.

Various compounds such as, for example morphine orN-isopropyl-noradrenaline are known to have anti-diuretic properties.Sympathomimetics, inter alia the di-amphetamine, have also recently beentested in this respect [Chemotherapie 6, page 363, (1963)] and onaccount of the results hitherto obtained, it has been assumed that inthis series the sympathomimetic and the anti-diuretic activities exhibita certain parallelism. In all these cases the anti-diuretic effectbecomes apparent only if doses are administered which have a stronganalgetic, broncholytic and blood pressure-depressing effect, orwhichstimulate the central nervous system. The anti-diuretic properties ofthe said compounds are, so to speak, side etfects and therapeuticallyuseless.

It has now been found that d()-N-alkyl-1-phenyl-2- aminoethanols of theformula R O H (CH 2 in which R is hydrogen, halogen, hydroxyl ortrifluoromethyl, or lower alkyl, alkoxy or alkylmercapto, and R ishydrogen or methyl, exhibit a marked anti-diuretic activity in animaltests whereby the excretion of water as Well as of salts is inhibited.Other effects, especially those on the central nervous system, occuronly if the dosages are many times higher. In contradistinction to thehitherto investigated other 1-phenyl-2-aminoethanols, the antidiureticeffect of these d()-N-alkyl-1-phenyl-2-aminoethanols is evidently notlinked with a sympathomimetic or central nervous system activity.

This fact and also the fact that the anti-diuretic activity isexclusively found in the d-forms of the saidN-alkyl-1-phenyl-2-aminoethanols were not to be foreseen. Thus, forexample, the hitherto likewise unknown 1-N-isopropyl-1-phenyl-2-aminoethanol and 1 )-N-tert.butyl-l-phenyl-Z-aminoethanol exhibit no anti-diuretic properties,even if the dosages are more than a hundred times higher. Thetherapeutic index of the d-compounds is considerably higher than that ofthe racemate, since the toxicity of the d-compound increases onlyslightly, compared with that of the racemate. Thus, surprisingly, theanit-diuretic activity is the essential and specific property of thesaid d(')-N-(alkyl)-1-phenyl-2-aminoethanols and can therefore beutilized in therapy.

The d()-N-alkyl-1-phenyl-2-aminoethanols can be produced from thecorresponding, partly known racemic compounds by resolution into theoptical isomers according to the methods customary for the purpose.Instead of the racemic alkyl-1-phenyl-2-aminoethanols, suitablefunctional derivatives of these compounds, for example their O-acylderivatives, may also be resolved into the optical isomers which arethen hydrolysed to give the free, optically active compounds.

3,344,188 Patented Sept. 26, 1967 A preferred method of resolution isthat via the salts with optically active acids, especially with1(+)-tartaric acid and 1()-dibenzoyl-tartaric acid. Alternatively, theproduction can also be carried out directly by synthesis with the use ofsuitable optically active starting compounds. Thus,d()-l-phenyl-Z-aminoethanols of the formula Q-CH-Cm-Nm in which R hasany of the above meanings, can be alkylated by treatment with reactiveesters of alcohols of the general formula HOC\ in which R has the abovesignificance, or it can be converted into the corresponding d()-N-alkyl-1-phenyl-2- aminoethanols by reductive alkylation in thepresence of acetone.

It is further possible to produce the desired d( )-N-alkyl-1-phenyl-2-aminoethanols from the corresponding d-N-alkyl-Z-phenyl-2-chloroethylamines by treatment with silver oxide. Thesame result is attained when the corresponding l-forms of thechloroethylamine derivatives are reacted with alkaline agents such as,e.g., alkali metal hydroxides, alkali metal carbonates or alkali metalacetates, the hydrolysis taking place with a Walden inversion. Finally,it is also possible to reduce d-mandelic acid-N-isopropylamide or-tert.butylamide, or d-mandelic acid-N- alkylamides which areappropriately substituted in the benzene nucleus, by means of lithiumaluminum hydride to form the desiredd(')-N-alkyl-1-phenyl-2-aminoethanols. The latter can be converted intowater-soluble salts by means of pharmaceutically acceptable non-toxicinorganic or organic acids.

The following examples are given for the purpose of illustrating theinvention.

Example I A solution of 722 g. of dl-N-tert.butyl-l-phenyl-2-aminoethanol (prepared by reacting styrene oxide with tert.butylamine inthe presence of water, M.P. 8990= C.) in 3000 ml. of methanol is addedto a solution of 600 g. of 1(+)-tartaric acid in 1000 ml. of water. Themixture is allowed to cool and to stand overnight, the separatedtartrate of 1(+) N tert.butyl-l-phenyl-2-aminoethanol obtained in anamount of 650 g. is filtered oif and recrystallized from a mixture ofmethanol and water; M.P. 98 C., [a] |-47.6 (methanol). The base isliberated by the addition of a sodium hydroxide solution andrecrystallized several times from ethyl acetate. 250 g. of pure1(+)-Ntert.butyl-l-phenyl-Z-aminoethanol are obtained; M.P. 106-107 C.,[a] -|80.2 (chloroform); M.P. of the hydrochloride 180-481 C.

The mother liquor of the tartrate previously filtered off, is renderedalkaline with a sodium hydroxide solution, the separated d-base filteredoff and recrystallized several times from ethyl acetate. 228 g. ofd()-N-tert.- butyl-1-phenyl-2-aminoethanol are obtained; M.P. 106- 107C., [u] -80.5 (chloroform); M.P. of the hydrochloride 180-181 (3., [a]49.4 (methanol).

Exam'ple II 191.6 g. of 1()-0,0-dibenzoyl-tartaric acid and 71.2 g. ofd1-N-isopropyl-l-phenyl-Z-aminoethanol are dissolved with heating in 240ml. of methanol and ml. of water, the mixture is cooled and allowed tostand at 0 C. for 24 hours. 131 g. of dibenzoyl tartrate crystallinefrom the solution and are recrystallized from ml. of

alcohol and 90 ml. of Water; M.P. 165-167 C., [c] 6Z (methanol). Thesalt is taken up in Water and rendered alkaline with a sodium hydroxidesolution. After filtering off, 26 g. of 1(+)-N-isopropyl-1-phenyl-Z-aminoethanol are obtained; M.P. 84-85 C. (ligroin), [a]- +75.4(chloroform); MP. of the hydrochloride 16l162 C.

Upon the addition of a sodium hydroxide solution, the mother liquor ofthe dibenzoyl tartrate previously filtered off yields 28 g. of cruded(-)-N-isopropyl-1-phenyl-2- aminoethanol which is purified by means ofd(-)-tartarie acid. For this purpose, 17.9 g. of crude d(-)-N-isopropyll-phenyl-Z-aminoethanol and g. of d(-)-tartaric acid aredissolved in 65 ml. of methanol, 3 ml. of water and 240 ml. of ethylacetate, the mixture is allowed to stand at C. for several hours, and bytrituration there are obtained 31 g. of the tartrate which isredissolved from 40 ml. of n-propanol and then yields g. of thedtartrate of d()-N-isopropyl-1-phenyl-2-aminoethanol; M.P. 161 C., [a];-58 (methanol). By adding a sodium hydroxide solution to this tartrate,the pure d(-)- N-isopropyl-l-phenyl-Z-aminoethanol is obtained; MP. 0,[ab -796 (chloroform); MP. of the hydrochloride 1'62-163 C.

Example III ml. of isopropylamine are added to a solution of 38 g. ofd()-mandelic acid methyl ester in 5O ml. of alcohol, and the mixture isallowed to stand at room temperature for eight days. It is thenconcentrated by evaporation in a vacuum at 2030 C., and the reactionproduct consisting of a mixture of d()-mandelic acid isopropylamide andd( )-mandelic acid isopropyl ester is reduced by the dropwise additionto an ethereal suspension of 14 g. of lithium alanate. The mixture isheated under reflux for 16 hours, decomposed with 28 ml. of a 20% sodiumhydroxide solution, filtered 01f with suction and References CitedUNITED STATES PATENTS 2,460,144 l/l949 Moore et al 260570.6 2,820,827l/l958 Ruschig et al 260570.6 2,938,921 5/1960 Mills 260570.6 2,967,1301/ 1961 Sanders et al. 167-65 3,028,492 4/ 1962 Wilbert et al 260-57063,048,633 8/1962 Russell et al. 260-570.6 X 3,081,230 3/1963 Weinstocket al. 167-65 3,236,892 2/1966 Petracek 260570.6

OTHER REFERENCES Devoghel et al.: Archives Intern, Pharmacodynamie, vol.26, pp. 471-4 (1960).

Osten: Arznemittel-Forschung, vol. 5, pp. 84-87 1955).

Read et al.: Journal Chemical Society London, 1930, pp. 2682-5.

Wagner et al.: Synthetic Organic Chemistry, pp. 660, 662 and 663 (1953).

CHARLES B. PARKER, Primary Examiner.

R. V. HINES, Assistant Examiner.

1. THE COMPOUND D(-)-N-TERT.BUTYL-L-PHENYL-2-AMINOETHANOL.
 2. THECOMPOUND D(-)-N-ISOPROPYL-L-PHENYL-2-AMINOETHANOL.